Skip Navigation LinksHome > June 2014 - Volume 32 - Issue 6 > Cardiovascular effects of phentermine and topiramate: a new...
Journal of Hypertension:
doi: 10.1097/HJH.0000000000000145
Reviews

Cardiovascular effects of phentermine and topiramate: a new drug combination for the treatment of obesity

Jordan, Jensa; Astrup, Arneb; Engeli, Stefana; Narkiewicz, Krzysztofc; Day, Wesley W.d; Finer, Nicke

Open Access
Supplemental Author Material
Article Outline
Collapse Box

Author Information

aInstitute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany

bDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Denmark

cDepartment of Hypertension and Diabetology, Medical University of Gdańsk, Dębinki, Gdańsk, Poland

dVIVUS, Inc., Mountain View, California, USA

eNational Centre for Cardiovascular Prevention and Outcomes, Institute for Cardiovascular Science, University College London, London, UK

Correspondence to Jens Jordan, MD, PhD, Director, Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany.Tel: +49 511 532 2821; fax: +49 511 532 162821; e-mail: jordan.jens@mh-hannover.de

Abbreviations: BP, blood pressure; b.p.m., beats per minute; Cmax, mean plasma maximum concentration; CHMP, Committee for Medicinal Products for Human Use; CI, confidence interval; CNS, central nervous system; EMA, European Medicines Agency; FDA, Food and Drug Administration; GABA, γ-aminobutyric acid; HDL-C, high-density lipoprotein cholesterol; IC50, half maximal inhibitory concentration; ITT-LOCF, intention-to-treat population with last observation carried forward; MACE, major adverse cardiac event; PHEN/TPM-ER, phentermine and topiramate extended-release; PNS, peripheral nervous system; Tmax, time to mean plasma maximum concentration; T2DM, type 2 diabetes mellitus

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Website ( http://www.jhypertension.com).

Received October 24, 2013

Revision received January 21, 2014

Accepted January 21, 2014

Collapse Box

Abstract

Weight loss can reduce the increased cardiovascular risk associated with obesity. Pharmacotherapy is a recognized weight loss treatment option; however, cardiovascular safety issues with some previous weight loss drugs raise concerns for newly approved pharmacotherapies. Phentermine is approved for short-term obesity treatment in conjunction with lifestyle modifications, but is commonly used chronically. Topiramate, approved for treating epilepsy and preventing migraines, also induces weight loss. A single-dose combination of low-dose phentermine and topiramate extended-release was recently approved by the United States Food and Drug Administration as an adjunct to lifestyle intervention for the chronic treatment of overweight/obese adults. This review summarizes and evaluates the cardiovascular risk/benefit profile associated with phentermine and topiramate, individually and in combination. Cardiovascular data associated with long-term use of phentermine and topiramate extended-release indicate that this combination may be a safe and effective option for reducing weight in overweight/obese patients at low-to-intermediate cardiovascular risk.
Back to Top | Article Outline

INTRODUCTION

The prevalence of obesity, defined as a BMI at least 30 kg/m2, has increased substantially in many countries [1]. Obesity poses significant cardiovascular health risks, such as increased risk of hypertension and cardiovascular disease, and can cause or exacerbate arterial hypertension; it is an important cause of treatment-resistant arterial hypertension [2,3]. Over the past decades, cardiovascular mortality has decreased in many countries, likely through use of statins, anti-hypertensives, and lifestyle modifications, including diet, exercise, and smoking cessation [4–7]. However, the rising prevalence of obesity and its related cardiovascular comorbidities could reduce, or even reverse, the impact of this achievement [8].

Modest weight loss of 5–10% in obese individuals improves cardiovascular risk markers, including blood pressure (BP) [9–11]. Consequently, the recently revised European Society of Hypertension guidelines recommend weight loss for obese hypertensive individuals [12]. The primary approach for the management of obesity and associated comorbidities is lifestyle intervention that includes energy restriction and increased physical activity; however, this approach is of modest efficacy and is associated with poor long-term patient adherence [13,14]. Additional interventions, such as bariatric surgery or pharmacotherapy, may be needed to achieve adequate sustained weight loss and cardiovascular risk reduction. Bariatric surgery effectively treats many weight-related comorbidities [15,16] and reduces all-cause mortality and mortality from myocardial infarction [15], but carries operative risks, and may not be appropriate for all patients [17].

Current licensed pharmacotherapies include phentermine hydrochloride (HCl), a sympathomimetic appetite-suppressant approved in the US for short-term (up to 12 weeks) treatment of obesity in conjunction with dietary and lifestyle modifications [18–20]; and orlistat, a gastric and pancreatic lipase inhibitor approved in the US and Europe for the long-term pharmacologic management of obesity [21–24]. Recently, the US Food and Drug Administration (FDA) has approved lorcaserin, a 5HT-2c agonist for chronic weight management in obese adult patients and overweight adult patients with at least one weight-related comorbidity as an adjunct to behavioural/lifestyle modifications [25]; and phentermine and topiramate extended-release (PHEN/TPM-ER), a once-daily combination therapy for chronic weight management in obese adult patients and overweight adult patients with at least one weight-related comorbidity as an adjunct to behavioural/lifestyle modifications [26].

Previously approved pharmacotherapies for treating obesity, including fenfluramine, which was often used in combination with phentermine, were found to have unacceptable cardiovascular risks that outweighed their potential weight-loss benefits [27–39]. These cardiovascular risks included, but were not limited to, increased risk of valvulopathy and pulmonary hypertension, which resulted in withdrawal from the market (Table 1) [27–39]. As a result, the US FDA now requires weight-loss pharmacotherapies to show no excess cardiovascular health risks, similar to treatments for type 2 diabetes mellitus (T2DM), and frequently requires the drug's manufacturer to conduct post-marketing safety studies, including long-term cardiovascular outcome trials [39,40]. The European Medicines Agency (EMA) expects new T2DM agents to produce no excess cardiovascular risk, requiring cardiovascular outcomes studies of at least 18–24 months or sufficiently sized meta-analysis data prior to granting marketing approval [41]. A recent concept paper from the Cardiovascular Working Party of the EMA Committee for Medicinal Products for Human Use (CHMP) indicates that the EMA is likely to adopt similar cardiovascular safety requirements for weight-loss pharmacotherapies in the near future [42]. This review aims to summarize and evaluate the cardiovascular benefit–risk profile associated with phentermine monotherapy, topiramate monotherapy, and their use in combination as PHEN/TPM-ER.

TABLE 1
TABLE 1
Image Tools
Back to Top | Article Outline

PHENTERMINE

Pharmacology and mechanism of action

Phentermine is an atypical amphetamine analogue that acts mainly to increase norepinephrine in the central nervous system (CNS), thereby suppressing appetite [43,44]. Phentermine potently releases norepinephrine [half maximal inhibitory concentration (IC50) = 39.4 nmol/l), but shows weaker effects on the release of dopamine (IC50 = 262 nmol/l) and serotonin (IC50 = 3511 nmol/l) [44]. The drug is a weak substrate or uptake inhibitor of the serotonin transporter [43,44] and has minimal effects on plasma serotonin in vivo[45]. At plasma concentrations associated with low doses of phentermine (e.g. less than 20 mg), there is insufficient exposure to activate either dopamine or serotonin receptors [44]. Although increased catecholamine release may be perceived to increase the potential for adverse cardiovascular effects, norepinephrine released in the brain can act presynaptically to diminish sympathetic activity through a so-called clonidine-like effect [46–51]. This mechanism may explain the observation that norepinephrine-uptake inhibitors, such as sibutramine, reboxetine, and desipramine, paradoxically decrease sensitivity to sympathetic stimuli [46–51].

Back to Top | Article Outline
Treatment of obesity and associated cardiovascular effects

Phentermine is the most widely used weight-loss pharmacotherapy in the US [52]; phentermine HCl, an immediate-release formulation that undergoes rapid dissolution and absorption in the gastrointestinal tract, is currently approved for use at a dose of 15.0–37.5 mg/day (adjusted to the patient's need) for the short-term (up to 12 weeks) treatment of obesity (Table 2) [19,20]. A phentermine resin that slowly releases active drug into the gastrointestinal system is also approved in the US for the short-term treatment of obesity (Table 2) [18]. Phentermine (either phentermine HCl 37.5 mg/day or phentermine resin 15–30 mg/day) has been evaluated as a monotherapy in several studies up to 36 weeks, and demonstrated reductions in body weight and waist circumference, and improved achievement of at least 5 or 10% weight loss relative to placebo [53–56]. Munro et al.[55] in 1968 studied weight loss with phentermine monotherapy (30 mg/day) in a 36-week, double-blind trial of overweight and obese women, and found significant weight loss with both continuous and intermittent regimens of phentermine treatment (12.2 and 13.0 kg, respectively) vs. a dummy vehicle (4.8 kg). Although no published studies describing long-term, randomized, controlled weight-loss trial data for phentermine are currently available, Hendricks et al.[57] in 2011 observed that patients (n = 300) treated with phentermine monotherapy, at doses ranging from 15 to 37.5 mg/day (mean dose 33.6 mg/day), showed significantly greater weight loss for 1 through 104 weeks of treatment (12.7%) compared with those on a low-carbohydrate ketogenic diet alone (8.4%; P = 0.0144).

TABLE 2
TABLE 2
Image Tools

The belief that phentermine increases heart rate and BP may be due to the assumption of amphetamine-like side effects based on similarities in drug pharmacology. However, in the observational study by Hendricks et al.[57], normotensive (14%), prehypertensive (52%), and hypertensive (34%) patients treated for a long term with phentermine (mean time on therapy of 92 weeks) demonstrated no significant increase in heart rate, as well as reductions in SBP and DBP that were similar to those in patients losing weight on a low-carbohydrate ketogenic diet alone. Furthermore, clinical studies using short-term (12 weeks) phentermine monotherapy have shown either reductions in heart rate and BP with phentermine treatment, perhaps linked to weight loss [56], or no significant changes in BP with phentermine treatment [53,54]. A study of patients taking phentermine for weight loss (n = 269) found no abuse potential or amphetamine-like withdrawal upon abrupt cessation of long-term treatment, even at doses higher than that commonly recommended and after treatment duration of up to 21 years [58]. Common side effects, as described in the phentermine-prescribing information, for short-term (12–14 weeks) use include dry mouth, insomnia, headache, dizziness, fatigue, tachycardia, and palpitations [18–20].

It should be noted that there were reports of valvular heart disease when phentermine was used in combination with fenfluramine or dexfenfluramine [28,30–33,59]. Of the 132 spontaneous reports with complete information, 113 (86%) met the cardiac valvulopathy case definition [59]. Of these 113 cases, 2 (2%) used fenfluramine alone, 16 (14%) dexfenfluramine alone, 89 (79%) a combination of fenfluramine and phentermine, and 6 (5%) a combination of all three drugs. There were no cases reported with phentermine monotherapy use [59]. Since none of these cases of cardiac valvulopathy was linked directly with phentermine treatment, the US FDA required the removal of fenfluramine and dexfenfluramine from the market, while maintaining its approval of phentermine as a monotherapy [39]. Ultimately, activity on the 5-HT2b receptor on heart valves was implicated as the primary mechanism associated with fenfluramine/dexfenfluramine-related valvulopathy [60]. Phentermine has no affinity for the 5-HT2b receptor and does not increase circulating serotonin [60,61]. Two case reports have described a temporal association between phentermine monotherapy and valvular heart disease or pulmonary arterial hypertension [62,63], but numerous pre-existing and concomitant morbidities in these cases have precluded any definitive conclusion about whether these were linked to treatment [64].

Back to Top | Article Outline

TOPIRAMATE

Pharmacology and mechanism of action

Topiramate immediate-release is a sulfamate-substituted monosaccharide used to treat epilepsy and to prevent migraines [65,66]. It is suggested that topiramate acts on kainate/alpha-amino-3-hydroxy-5-methylisoxozole-4-propionic acid glutamate receptors. Moreover, topiramate appears to block voltage-dependent sodium channels, augment γ-aminobutyric acid activity (GABA-A), and inhibit carbonic anhydrase isoenzymes II and IV, although the mechanism of action for topiramate's effects on weight is unknown [65,66]. Topiramate may decrease food intake via effects of carbonic-anhydrase inhibition on taste [67,68], or through its effects on GABA transmission, since GABA-A receptor activation [69] and the interaction between GABA and leptin pathways [70] are known to mediate effects on appetite and metabolism. Topiramate may also affect energy expenditure (based on preclinical data) [71].

Back to Top | Article Outline
Current indications, treatment of obesity, and cardiovascular effects

Topiramate immediate-release is currently approved at doses of 100–400 mg/day (titrated over 6 weeks) as monotherapy for treating seizures in adults and children over age 6, with other medicines to treat seizures in adults and children aged at least 2 years, or for preventing migraines in adults (Table 2) [65,66]. Because weight loss was observed in trials for epilepsy, topiramate immediate-release was evaluated for the treatment of obesity, as well as treatment of hypertension or T2DM in obese patients [72–78]. A 6-month, placebo-controlled, randomized trial of 385 obese patients demonstrated weight loss of 2.6% with placebo, and 5.0, 4.8, 6.3, and 6.3% in patients randomized to topiramate immediate-release 64, 96, 192, or 384 mg/day along with lifestyle intervention, respectively [73]. Doses were gradually increased over 12 weeks and tapered at the end of trial [73]. All topiramate immediate-release doses elicited greater weight loss than placebo [73]. A long-term study (up to 60 weeks) evaluated the safety and efficacy of topiramate immediate-release for weight maintenance in obese patients who had lost at least 8% body weight after 8 weeks on a low-calorie diet [72]. After 44 weeks of treatment, patients treated with topiramate immediate-release had lost 15.4 and 16.5% of their enrolment body weight at 96 and 192 mg/day doses, respectively (vs. 8.9% with placebo), and more patients treated with topiramate immediate-release lost at least 15% body weight than those treated with placebo [72]. In another placebo-controlled, randomized clinical trial of 531 obese patients with hypertension, patients treated with topiramate immediate-release experienced weight loss of 5.9 and 6.5% at 96 and 192 mg/day, respectively (vs. 1.9% with placebo), as well as reductions in BP after 28 weeks of treatment [SBP: −8.6 and −9.7 mmHg, respectively, vs. −4.9 mmHg with placebo (P = NS); DBP: −5.5 and −6.3 mmHg, respectively, vs. −2.1 mmHg with placebo (P < 0.015)] [76]. Subsequent to these studies of topiramate immediate-release, an extended-release formulation of topiramate was developed potentially to enhance tolerability while simplifying dosing [78], but this formulation was never submitted for regulatory approval.

Topiramate, like other carbonic anhydrase inhibitors, may produce CNS and peripheral nervous system (PNS) effects, such as paraesthesias, acute myopia, blurred vision, redness of the sclera, photophobia, and eye discomfort resulting from secondary angle-closure glaucoma, as well as psychiatric and neurologic disturbances, including fatigue, somnolence, depression, and difficulties with concentration and memory [65,66]. Although in-vitro evidence has suggested the potential for topiramate to be arrhythmogenic [79], data indicate that topiramate does not increase the risk of sudden unexpected death due to cardiac arrhythmia in epilepsy patients [80]. Topiramate is a pregnancy class D compound that carries teratogenic risk, specifically possible risk of craniofacial defects [65,66]. Data from patients (mostly adults with partial-onset seizures) in double-blind, placebo-controlled studies receiving doses of 200–1000 mg/day (N = 360) and long-term studies (up to approximately 5 years; N = 1001) showed CNS treatment-related adverse events that were dose-dependent, with a greater frequency at topiramate dosages greater than 200–600 mg/day, and occurring early in treatment [81]. The most common adverse events in weight-loss trials of obese/overweight patients were dose-related and in the PNS, CNS, or psychiatric categories (including paraesthesia, hypoaesthesia, memory/attentional difficulties, dizziness, neuropathy, anxiety, depression, headache, fatigue, insomnia, and somnolence) [72–78]. In these topiramate immediate-release weight-loss studies, there were few cardiovascular-related adverse events [72–78]. Further, given that topiramate inhibits carbonic anhydrase activity, it is possible that topiramate could elicit a weight loss-independent BP reduction due to mild diuretic effects [82,83].

Back to Top | Article Outline

PHENTERMINE AND TOPIRAMATE EXTENDED-RELEASE FOR THE TREATMENT OF OBESITY

Pharmacology and mechanism of action

On the basis of the weight loss achieved with phentermine and topiramate as individual agents, and the notion that a combination of these agents at low doses might have additive or synergistic effects, thereby providing improved efficacy and safety over the products individually, a combination of PHEN/TPM-ER was developed for once-daily oral dosing to enhance weight loss and to improve weight-related comorbidities in overweight and/or obese patients [84–89]. In this low-dose formulation, phentermine [mean plasma maximum concentration (Cmax) 49.1 ng/ml; time to median plasma maximum concentration (Tmax) 6 h] is readily absorbed and immediately released to provide effects early in the day, whereas topiramate extended-release (Cmax 1020 ng/ml; Tmax 9 h) is released later and provides effects through later periods of the day [26,90]. PHEN/TPM-ER is currently approved at doses of 3.75 mg/23 mg, 7.5 mg/46 mg and 15 mg/92 mg for chronic weight management in obese and overweight adults with at least one weight-related comorbidity (Table 2) [26].

Back to Top | Article Outline
Clinical trials

The efficacy, safety, and tolerability of PHEN/TPM-ER were assessed in overweight and obese patients with comorbidities in two 1-year, randomized, double-blind, placebo-controlled phase 3 studies [84,86]. EQUIP included 1267 severely obese adults (≤70 years of age and BMI ≥35 kg/m2; patients with T2DM were excluded) [84]. CONQUER included 2487 overweight and obese adults (≤70 years of age; BMI ≥27 kg/m2 and ≤45 kg/m2) with at least two weight-related comorbidities, including hypertension and T2DM [86]. An extension study was also performed, which evaluated patients from select CONQUER sites who elected to continue their blinded, randomized treatments in the study for an additional 52 weeks (SEQUEL) [87]. In a fourth study, adults with T2DM were evaluated in a 28-week extension of a 28-week double-blind, placebo-controlled phase 2 trial (DM-230; 56 weeks total) [88]. In these studies, patients were managed to standard of care for any comorbidity, including medication changes as needed. All patients received dietary and lifestyle counselling based on the Lifestyle, Exercise, Attitudes, Relationships, Nutrition (LEARN) programme [91], including guidance to reduce daily caloric intake by 500 kilocalories, increase water consumption, and increase physical activity [84,86,87]. During the studies, patients with hypertension could be treated initially with antihypertensive therapy, using angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers; if patients were already taking these agents, calcium channel blockers, beta blockers, or thiazide diuretics could be added [92]. Patients whose BP exceeded 160/100 mmHg on three consecutive visits or who underwent increases in either dose or number of antihypertensives on each of these visits were discontinued from the study and referred back to their primary care physician [92]. Similarly, patients with T2DM or dyslipidaemia could also have their medications adjusted to achieve standard of care [92]. Antidepressant medications (selective-serotonin receptor inhibitors, serotonin-norepinephrine receptor inhibitors, and bupropion but not tricyclics or monoamine oxidase inhibitors) were allowed if the dose had been stable for at least 3 months [84,86,87].

Back to Top | Article Outline
Weight loss (1-year and 2-year studies)

In the 1-year pooled analysis of the EQUIP (n = 1267) [84] and CONQUER (n = 2487) [86] studies, and in DM-230 (n = 130), PHEN/TPM-ER was associated with significant and sustained percentage weight loss in overweight and obese patients when compared with placebo [intention-to-treat population with last observation carried forward (ITT-LOCF); Fig. 1] [88,92]. A significantly greater proportion of patients receiving PHEN/TPM-ER also achieved at least 5% weight loss after 56 weeks of treatment in the phase 2 and 3 studies when compared with placebo [92]. Similarly, patients showed significant, sustained percentage and categorical weight loss through 108 weeks in the 2-year cohort of the SEQUEL extension study [87].

FIGURE 1
FIGURE 1
Image Tools
Back to Top | Article Outline
Changes in heart rate and blood pressure (1-year and 2-year cohorts, safety set)

In the 1-year cohort, weight loss induced by PHEN/TPM-ER was associated with significant reductions in SBP (P< 0.0001 for PHEN/TPM-ER 7.5/46 and 15/92 doses vs. placebo; not significant for PHEN/TPM-ER 3.75/23 vs. placebo) and DBP (P< 0.005 for PHEN/TPM-ER 7.5/46 and 15/92 doses vs. placebo; not significant for PHEN/TPM-ER 3.75/23 vs. placebo; Fig. 2) [88,89]. Reductions in BP occurred in parallel with slight increases in heart rate in all PHEN/TPM-ER groups [mean change ± SD) of 1.3 ± 10.3 beats per minute (b.p.m.), 0.6 ± 10.2 b.p.m. and 1.6 ± 10.3 b.p.m. for PHEN/TPM-ER 3.75/23, 7.5/46, and 15/92 groups, respectively], which was significant vs. placebo (0.0 ± 10.2 b.p.m.) only in the PHEN/TPM-ER 15/92 group (P< 0.0001; Fig. 2) [88,89]. However, among patients with the highest heart rate at baseline (>90 b.p.m.), most showed reductions in heart rate at the 1-year endpoint (Fig. 3) [88].

FIGURE 2
FIGURE 2
Image Tools
FIGURE 3
FIGURE 3
Image Tools

Results were similar, although less pronounced in the 2-year cohort based on management to standard of care and medication changes; all PHEN/TPM-ER-treated patients showed reductions in SBP and DBP (see Table S1, Supplemental Digital Content, http://links.lww.com/HJH/A339) [87,92]. At 2 years, there was also a significant net reduction in concomitant antihypertensive medication use in patients treated with PHEN/TPM-ER, whereas placebo-treated patients experienced a net increase in antihypertensive medication use (P = 0.0165 for between-group differences; see Table S1, Supplemental Digital Content, http://links.lww.com/HJH/A339) [93]. The slight mean increases in heart rate vs. baseline with PHEN/TPM-ER treatment observed in the 1-year cohort were still evident after 2 years of treatment, but were not significant compared with placebo (see Table S1, Supplemental Digital Content, http://links.lww.com/HJH/A339) [92].

Back to Top | Article Outline
Changes in rate pressure product (1-year and 2-year cohorts, safety set)

Increased myocardial oxygen demand is the putative mechanism by which increased heart rate promotes cardiac ischaemia in patients with macrovascular or microvascular coronary disease [94]. The rate pressure product, defined as the product of heart rate and SBP divided by 1000, is related to myocardial oxygen demand, and was decreased in the placebo group and each of the PHEN/TPM-ER groups in the 1-year cohort (with greatest reductions seen in the PHEN/TPM-ER 7.5/46 dose; Fig. 2c) [88] and the 2-year cohort (see Table S1, Supplemental Digital Content, http://links.lww.com/HJH/A339) [92]. These data suggest that the mild heart rate increase with PHEN/TPM-ER over 2 years may not increase myocardial oxygen demand.

Back to Top | Article Outline
Weight loss and changes in cardiovascular risk factors in patients with dyslipidaemia or hypertension

In patients with dyslipidaemia or hypertension at baseline participating in the 56-week CONQUER study, PHEN/TPM-ER induced significantly greater, dose-related mean percentage weight loss vs. placebo (P < 0.0001), with a greater proportion of PHEN/TPM-ER-treated patients achieving at least 5, 10, and 15% weight loss [85]. PHEN/TPM-ER treatment was associated with significant improvements in serum triglyceride, high-density lipoprotein cholesterol (HDL-C), and non-HDL-C levels vs. placebo (P < 0.05) in patients with dyslipidaemia at week 56, along with a net reduction in lipid-lowering medication use [85]. In patients with hypertension at baseline, PHEN/TPM-ER-treated patients showed significant improvements in BP at week 56 [SBP: −6.9 and −9.1 mmHg for PHEN/TPM-ER 7.5/46 and 15/92, respectively, vs. −4.9 mmHg for placebo (P < 0.05); DBP: −5.2 and −5.8 mmHg for PHEN/TPM-ER 7.5/46 and 15/92, respectively, vs. −3.9 mmHg for placebo (P < 0.05)], as well as a net decrease in antihypertensive medication use (P < 0.0001 for between-group differences) [85]. Similar to the overall CONQUER population, a slight increase in heart rate (0.1 to 1.3 b.p.m.) was observed in the dyslipidaemia and hypertension subgroups [85,86].

In pooled data of hypertensive patients from the two 1-year studies (CONQUER and EQUIP), reductions in SBP and DBP were seen in all PHEN/TPM-ER groups, whereas heart rate was slightly increased in the 7.5/46 and 15/92 dose groups (Table 3) [92]. At endpoint in the 2-year cohort, patients with hypertension at baseline showed reductions in SBP and DBP. Concomitant antihypertensive medication use in PHEN/TPM-ER-treated patients was significantly reduced, compared to a net increase in antihypertensive medication use in the placebo group (P = 0.0012 for between-group differences; see Figure S1, Supplemental Digital Content, http://links.lww.com/HJH/A339) [93].

TABLE 3
TABLE 3
Image Tools
Back to Top | Article Outline
Safety in all exposed patients

Common adverse events in PHEN/TPM-ER clinical trials were paraesthesia, dizziness, dysgeusia, insomnia, constipation, and dry mouth. Adverse events were generally dose-related and mild to moderate in severity, occurring mostly during the titration period [26,84,86–88]. PHEN/TPM-ER contraindications are similar to those of phentermine and topiramate monotherapy (Table 2) [18–20,26,65,66].

Cardiac arrhythmia-related adverse events reported by patients (as defined by mapping to the Medical Dictionary for Regulatory Activities Cardiac Disorders System Organ Class) were palpitations, increased heart rate, and tachycardia, and occurred in between 0.1 and 2.4% of patients (palpitations: 0.8, 0.8, 2.4, and 1.7% for placebo and PHEN/TPM-ER 3.75/23, 7.5/46, and 15/92, respectively; heart rate increased: 0.1, 0.0, 0.4, and 0.8%, respectively; tachycardia: 0.1, 0.4, 0.4, and 0.7%, respectively) [92]. There were low rates of serious adverse events classified as cardiac disorders [92].

Back to Top | Article Outline
Cardiac events in all exposed patients

Within the 1-year safety cohort, 752 (19.8%) patients were considered to have low cardiovascular risk, 2498 (65.6%) had moderate cardiovascular risk, and 14.6% were in a high cardiovascular risk category [modified Adult Treatment Panel (ATP) III criteria] [92]. In the 1 and 2-year safety cohorts, the different outcome definitions of major adverse cardiac events (MACEs) each had a hazard ratio (PHEN/TPM-ER vs. placebo) below 1.0, ranging from 0.49 [95% confidence interval (CI) 0.19, 1.25] for US FDA MACE to 0.84 (95% CI 0.26, 2.64) for the traditional MACE composite endpoint (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke; Table 4) [92]. The traditional MACE composite endpoint (cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke) was incident in 12 of the 4323 patients (5/1742 in the placebo group and 7/2581 in the PHEN/TPM-ER group; Table 4); the wide CI found in the analysis of the traditional MACE composite endpoint indicates that a larger sample is required to sufficiently address this issue [92]. The hazard ratio for the broadest MACE criteria (cardiovascular/neurovascular serious adverse events), which had a total of 43 events (20/1742 in the placebo group and 23/2581 in the PHEN/TPM-ER group), had a 95% CI with an upper bound of 0.98, representing a statistically significant reduction in cardiovascular risk (Table 4) [92]. At this time, there are too few events from clinical trial data to draw firm conclusions about decreases or increases in MACE in patients treated with PHEN/TPM-ER; however, available data do not indicate any increased cardiovascular risk associated with PHEN/TPM-ER. A cardiovascular outcomes trial is planned by the drug's manufacturer, in accordance with one of the US FDA's post-marketing study requirements [95]. The EMA's CHMP has indicated that a long-term cardiovascular outcomes trial would be necessary to support PHEN/TPM-ER centralized approval in Europe [96]. In addition to the planned long-term cardiovascular outcomes trial, future research might beneficially be directed at exploring the effects of PHEN/TPM-ER on surrogate physiologic measures of cardiovascular health, such as endothelial function, and in obese individuals with resistant hypertension.

TABLE 4
TABLE 4
Image Tools
Back to Top | Article Outline

CLINICAL PERSPECTIVE

There is a current unmet need for an effective weight-loss pharmacotherapy that can be used for long term for the many patients unable to attain or to maintain weight loss through dietary interventions and exercise. Given the increased cardiovascular and metabolic risk in this patient population, obesity pharmacotherapies must present minimal unwanted or adverse cardiovascular risks, which if present, should be outweighed by their other cardiovascular-related benefits. The rationale of combining low doses of PHEN/TPM-ER is to minimize side effects while maintaining weight loss efficacy. However, the treatment is not without side effects. For example, the topiramate extended-release component can induce paraesthesia and taste change, likely through carbonic anhydrase inhibition. Topiramate cannot be used by pregnant women due to teratogenic risks. The phentermine component can produce adrenergic symptoms, such as dry mouth. However, it is clinically reassuring that weight loss induced by PHEN/TPM-ER was associated with improved BP through 1 and 2 years of treatment. Although small, usually transient, increases in heart rate were observed in some patients, there were concurrent reductions in BP and rate pressure product, suggesting that, when used in conjunction with lifestyle modifications, PHEN/TPM-ER may represent a safe and effective therapy for the management of obesity in the patient populations studied (those with low-to-intermediate cardiovascular risk). The influences of PHEN/TPM-ER treatment on cardiovascular outcomes are currently being tested in a large multinational trial.

Back to Top | Article Outline

ACKNOWLEDGEMENTS

We would like to acknowledge and thank The Lockwood Group for editorial assistance.

Funding for this manuscript was provided by VIVUS, Inc.

Back to Top | Article Outline
Conflicts of interest

J.J. has participated in advisory boards for Boehringer-Ingelheim, Sanofi-Aventis, and Novartis, has been a consultant for Sanofi-Aventis and Novartis, and has received research support from Novartis, Sanofi-Aventis, CVRx, Inc., and Boehringer-Ingelheim. A.A. has been a consultant for Arena Pharmaceuticals, Basic Research, Gelesis, Inc., Doyen Medical Inc., Novo Nordisk, Orexigen Therapeutics Inc., Rhythm Pharmaceuticals, S-Biotek, Twinlab, and VIVUS, Inc. S.E. has received research support for clinical trials from Novartis. K.N. has participated in advisory boards for Medtronic and Boehringer-Ingelheim, has been a consultant for Medtronic, and has received research support for clinical trials for Abbott and Daiichi Sankyo. K.N. has also received honoraria for speakers/chairmanship at meetings for Abbott, Adamed, Astra Zeneca, Bayer, Berlin-Chemie, Boehringer-Ingelheim, Daiichi-Sankyo, Krka, Menarini, Novartis, Pfizer, Polpharma, Sanofi-Aventis, and Servier. W.W.D. is an employee of VIVUS, Inc. N.F. has been a consultant to VIVUS, Inc., and has participated in advisory board(s) for Novo Nordisk, Abbott, and Sanofi-Aventis, is a stockholder of Counterweight plc, and is an employee of UCLH NHS Trust.

Back to Top | Article Outline
Reviewers’ Summary Evaluations
Back to Top | Article Outline

Reviewer 1

This review showed that combining low doses of phentermine and topiramate for the treatment of obesity minimized side effects while maintained weight loss efficacy. The side effects were paraesthesia, taste changes and dry mouth.

Weight loss induced by the combination was associated with improved BP through one and two years of treatment. A small, usually transient increase in heart rate was observed. However, reductions in BP and rate pressure product were seen suggesting that when used in conjunction with lifestyle modifications, the combination may represent a safe and effective therapy for the management of obesity. A large multinational trial concerning cardiovascular outcomes is ongoing.

Back to Top | Article Outline

Reviewer 2

Combination drug treatment based on phentermine and topiramate has been recently approved by the FDA for the treatment of overweight and obesity. The paper by Jordan et al. provides an updated review on the cardiovascular effects of this new therapeutic approach which, along with its significant and sustained weight loss effects, improves triglycerides and HDL cholesterol and significantly decreases blood pressure values throughout the body weight reduction.

The information available so far on the impact the drug has on cardiovascular events (limited at present at the one year follow-up) confirms the favourable effects the drug has on cardiovascular risk.

Back to Top | Article Outline

REFERENCES

1. World Health Organization Obesity and overweight fact sheet No 311. (WWW document). ; 2013. http://www.who.int/mediacentre/factsheets/fs311/en/index.html

http://www.who.int/mediacentre/factsheets/fs311/en/index.html


2. Nguyen T, Lau DC. The obesity epidemic and its impact on hypertension. Can J Cardiol. 2012; 28:326–333.

3. Jordan J, Yumuk V, Schlaich M, Nilsson PM, Zahorska-Markiewicz B, Grassi G, et al. Joint statement of the European Association for the Study of Obesity and the European Society of Hypertension: obesity and difficult to treat arterial hypertension. J Hypertens. 2012; 30:1047–1055.

4. Gerber Y, Jacobsen SJ, Frye RI, Weston SA, Killian JM, Roger VL. Secular trends in deaths from cardiovascular diseases: a 25-year community study. Circulation. 2006; 113:2285–2292.

5. Sytkowski PA, Kannel WB, D’Agostino RB. Changes in risk factors and the decline in mortality from CVD. The Framingham Heart Study. N Engl J Med. 1990; 322:1635–1641.

6. Ford ES, Capewell S. Proportion of the decline in CV mortality disease due to prevention vs. treatment: public health vs. clinical care. Annu Rev Public Health. 2011; 32:5–22.

7. Franklin BA, Cushman M. Recent advances in preventive cardiology and lifestyle medicine. Circulation. 2011; 123:2274–2283.

8. Stewart ST, Cutler DM, Rosen AB. Forecasting the effects of obesity and smoking on U.S. life expectancy. N Engl J Med. 2009; 361:2252–2260.

9. Torgerson JS, Sjostrom L. The Swedish Obese Subjects (SOS) study: rationale and results. Int J Obes Relat Metab Disord. 2001; 25:(Suppl 1):S2–S4.

10. Caterson ID, Finer N, Coutinho W, Van Gaal LF, Maggioni AP, Torp-Pedersen C, et al. Maintained intentional weight loss reduces cardiovascular outcomes: results from the Sibutramine Cardiovascular OUTcomes (SCOUT) trial. Diabetes Obes Metab. 2012; 14:523–530.

11. Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, Bertoni AG, et al. Benefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetes. Diabetes Care. 2011; 34:1481–1486.

12. Mancia G, Fagard R, Narkiewicz K, Redón J, Zanchetti A, Böhm M, et al. Task Force Members 2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013; 31:1281–1357.

13. Coons MJ, Roehrig M, Spring B. The potential of virtual reality technologies to improve adherence to weight loss behaviors. J Diabetes Sci Technol. 2011; 5:340–344.

14. Scheen AJ. The future of obesity: new drugs versus lifestyle interventions. Expert Opin Investig Drugs. 2008; 17:263–267.

15. Sjöström L, Peltonen M, Jacobson P, Sjöström CD, Karason K, Wedel H, et al. Bariatric surgery and long-term cardiovascular events. J Am Med Assoc. 2012; 307:56–65.

16. Colquitt JL, Picot J, Loveman E, Clegg AJ. Surgery for obesity. Cochrane Database Syst Rev. 2009; CD003641

17. Greenstein AJ, Wahed AS, Adeniji A, Courcoulas AP, Dakin G, Flum DR, et al. Prevalence of adverse intraoperative events during obesity surgery and their sequelae. J Am Coll Surg. 2012; 215:271–277.

18. Ionamin. Package insert. Smyrna, GA, USA: UCB, Inc.; December 2012 .

19. Adipex. Package insert. Sellersville, PA, USA: Teva Pharmaceuticals USA; July 2005 .

20. Suprenza. Package insert. Cranford, NJ, USA: Akrimax Pharmaceuticals, LLC; December 2012 .

21. Xenical. Package insert. South San Francisco, CA, USA: Genentech; January 2012 .

22. Xenical. Patient information leaflet. Shire Park, Welwyn Garden City, UK: Roche Registration Limited; April 2012 .

23. Alli. Summary of product information. Greenford, Middlesex, UK: Glaxo Group Limited; July 2007 .

24. Alli. Package insert. Moon Township, PA, USA: GlaxoSmithKline Consumer Healthcare; February 2007 .

25. Belviq. Package insert. Zofingen, Switzerland: Arena Pharmaceuticals; June 2012 .

26. Qsymia®. Phentermine and topiramate extended-release [package insert]. Mountain View, CA, USA: VIVUS, Inc.; April 2013 .

27. Derosa G, Maffioli P. Antiobesity drugs: a review about their effects and their safety. Expert Opin Drug Saf. 2012; 11:459–471.

28. Jick H, Vasilakis C, Weinrauch LA, Meier CR, Jick SS, Derby LE. A population-based study of appetite-suppressant drugs and the risk of cardiac-valve regurgitation. N Engl J Med. 1998; 339:719–724.

29. Padwal RS, Majumdar SR. Drug treatments for obesity: orlistat, sibutramine, and rimonabant. Lancet. 2007; 369:71–77.

30. Rich S, Rubin L, Walker AM, Schneeweiss S, Abenhaim L. Anorexigens and pulmonary hypertension in the United States: results from the surveillance of North American pulmonary hypertension. Chest. 2000; 117:870–874.

31. Sachdev M, Miller WC, Ryan T, Jollis JG. Effect of fenfluramine-derivative diet pills on cardiac valves: a meta-analysis of observational studies. Am Heart J. 2002; 144:1065–1073.

32. Schembre DB, Boynton KK. Appetite-suppressant drugs and primary pulmonary hypertension. N Engl J Med. 1997; 336:510–511.

[author reply 512–513]


33. Tellier P. Fenfluramines, idiopathic pulmonary primary hypertension and cardiac valve disorders: facts and artifacts. Ann Med Interne (Paris). 2001; 152:429–436.

34. Topol EJ, Bousser MG, Fox KA, Creager MA, Despres JP, Easton JD, et al. Rimonabant for prevention of cardiovascular events (CRESCENDO): a randomised, multicentre, placebo-controlled trial. Lancet. 2010; 376:517–523.

35. Torp-Pedersen C, Caterson I, Coutinho W, Finer N, Van Gaal L, Maggioni A, et al. Cardiovascular responses to weight management and sibutramine in high-risk subjects: an analysis from the SCOUT trial. Eur Heart J. 2007; 28:2915–2923.

36. Kang JG, Park CY. Antiobesity drugs: a review about their effects and safety. Diabetes Metab J. 2012; 3:13–25.

37. Nutrition Committee of the Royal College of Physicians of London. Antiobesity drugs: guidance on appropriate prescribing and management (WWW document). ; 2003. http://www.rcplondon.ac.uk/sites/default/files/documents/antiobesity_reportweb.pdf

http://www.rcplondon.ac.uk/sites/default/files/documents/antiobesity_reportweb.pdf


38. Medicines and Healthcare Products Regulatory Agency. European withdrawal of anorectic agents/appetite suppressants: new legal developments, no new safety issues: licences for phentermine and amfepramone being withdrawn May 2001 (WWW document). ; 2001. http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON019540

http://www.mhra.gov.uk/Safetyinformation/Safetywarningsalertsandrecalls/Safetywarningsandmessagesformedicines/CON019540


39. U.S. Department of Health and Human Services. Public Health Service. Food and Drug Administration. Background memorandum: the role of cardiovascular assessment in the pre and postapproval settings for drugs developed for the treatment of obesity (WWW document). ; 2012. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm297240.pdf

http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/endocrinologicandmetabolicdrugsadvisorycommittee/ucm297240.pdf


40. U.S. Department of Health and Human Services. Food and Drug Administration. Center for Drug Evaluation and Research (CDER). Guidance for industry: diabetes mellitus: evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes (WWW document). ; 2008. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm071627.pdf


41. European Medicines Agency. Committee for Medicinal Products for Human Use. Guideline on clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus (WWW document). ; 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/06/WC500129256.pdf


42. European Medicines Agency. Committee for Medicinal Products for Human Use. Concept paper on the need for revision of the guideline of medical products used in weight control (WWW document). ; 2012. http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/10/WC500133166.pdf

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/10/WC500133166.pdf


43. Rothman RB, Ayestas MA, Dersch CM, Baumann MH. Aminorex, fenfluramine, and chlorphentermine are serotonin transporter substrates. Implications for primary pulmonary hypertension. Circulation. 1999; 100:869–875.

44. Rothman RB, Baumann MH, Dersch CM, Romero DV, Rice KC, Carroll I, Partilla JS. Amphetamine-type central nervous system stimulants release norepinephrine more potently than they release dopamine and serotonin. Synapse. 2001; 39:32–41.

45. Zolkowska D, Rothman RB, Baumann MH. Amphetamine analogs increase plasma serotonin: implications for cardiac and pulmonary disease. J Pharmacol Exp Ther. 2006; 318:604–610.

46. Birkenfeld AL, Schroeder C, Boschmann M, Tank J, Franke G, Luft FC, et al. Paradoxical effect of sibutramine on autonomic cardiovascular regulation. Circulation. 2002; 106:2459–2465.

47. Eisenhofer G, Saigusa T, Esler MD, Cox HS, Angus JA, Dorward PK. Central sympathoinhibition and peripheral neuronal uptake blockade after desipramine in rabbits. Am J Physiol. 1991; 260:(4 Pt 2):R824–R832.

48. Jordan J, Scholze J, Matiba B, Wirth A, Hauner H, Sharma AM. Influence of sibutramine on blood pressure: evidence from placebo-controlled trials. Int J Obes. 2005; 29:509–516.

49. Schroeder C, Tank J, Boschmann M, Diedrich A, Sharma AM, Biaggioni I, et al. Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance. Circulation. 2002; 105:347–353.

50. Tank J, Schroeder C, Diedrich A, Szczech E, Haertter S, Sharma AM, et al. Selective impairment in sympathetic vasomotor control with norepinephrine transporter inhibition. Circulation. 2003; 107:2949–2954.

51. Esler MD, Wallin G, Dorward PK, Eisenhofer G, Westerman R, Meredith I, et al. Effects of desipramine on sympathetic nerve firing and norepinephrine spillover to plasma in humans. Am J Physiol. 1991; 260:R817–R823.

52. Hendricks EJ, Rothman RB, Greenway FL. How physician obesity specialists use drugs to treat obesity. Obesity (Silver Spring). 2009; 17:1730–1735.

53. Kang JG, Park CY, Kang JH, Park YW, Park SW. Randomized controlled trial to investigate the effects of a newly developed formulation of phentermine diffuse-controlled release for obesity. Diabetes Obes Metab. 2010; 12:876–882.

54. Kim KK, Cho HJ, Kang HC, Youn BB, Lee KR. Effects on weight reduction and safety of short-term phentermine administration in Korean obese people. Yonsei Med J. 2006; 47:614–625.

55. Munro JF, MacCuish AC, Wilson EM, Duncan LJ. Comparison of continuous and intermittent anorectic therapy in obesity. BMJ. 1968; 1:352–354.

56. Valle-Jones JC, Brodie NH, O’Hara H, O’Hara J, McGhie RL. A comparative study of phentermine and diethylpropion in the treatment of obese patients in general practice. Pharmatherapeutica. 1983; 3:300–304.

57. Hendricks EJ, Greenway FL, Westman EC, Gupta AK. Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity. Obesity (Silver Spring). 2011; 19:2351–2360.

58. Hendricks EJ, Srisurapanont M, Schmidt SL, Haggard M, Souter S, Mitchell CL, et al. Addiction potential of phentermine prescribed during long-term treatment of obesity. Int J Obes (Lond). 2014; 38:292–298.

59. Center for Disease Control Cardiac valvulopathy associated with exposure to fenfluramine or dexfenfluramine: U.S. Department of Health and Human Services Interim Public Health Recommendations. MMWR Morb Mortal Wkly Rep. 1997; 46:1061–1066.

60. Rothman RB, Baumann MH. Serotonergic drugs and valvular heart disease. Expert Opin Drug Saf. 2009; 8:317–329.

61. Whigham LD, Dhurandhar NV, Rahko PS, Atkinson RL. Comparison of combinations of drugs for treatment of obesity: body weight and echocardiographic status. Int J Obes (Lond). 2007; 31:850–857.

62. Bang WD, Kim JY, Yu HT, Sung-Soo C, Jang JY, Oh CM, et al. Pulmonary hypertension associated with use of phentermine. Yonsei Med J. 2010; 51:971–973.

63. Yosefy C, Berman M, Beeri R. Cusp tear in bicuspid aortic valve possibly caused by phentermine. Int J Cardiol. 2006; 106:262–263.

64. Hendricks EJ, Rothman RB. Re: pulmonary hypertension associated with use of phentermine? Yonsei Med J. 2011; 52:869–870.

65. Topamax. Package insert. Titusville, NJ, USA: Janssen Pharmaceuticals, Inc.; October 2012 .

66. Topamax. Package leaflet. High Wycombe, Bucks: Janssen-Cilag Ltd.; September 2012 .

67. Silberstein SD, Neto W, Schmitt J, Jacobs D. MIGR-001 Study Group Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol. 2004; 61:490–495.

68. Sugrue MF. Pharmacological and ocular hypotensive properties of topical carbonic anhydrase inhibitors. Prog Retin Eye Res. 2000; 19:87–112.

69. Turenius CI, Htut MM, Prodon DA, Ebersole PL, Ngo PT, Lara RN, et al. GABA(A) receptors in the lateral hypothalamus as mediators of satiety and body weight regulation. Brain Res. 2009; 1262:16–24.

70. Xu Y, O’Brien WG 3rd, Lee CC, Myers MG Jr, Tong Q. Role of GABA release from leptin receptor-expressing neurons in body weight regulation. Endocrinology. 2012; 153:2223–2233.

71. Picard F, Deshaies Y, Lalonde J, Samson P, Richard D. Topiramate reduces energy and fat gains in lean (Fa/?) and obese (fa/fa) Zucker rats. Obes Res. 2000; 8:656–663.

72. Astrup A, Caterson I, Zelissen P, Guy-Grand B, Carruba M, Levy B, et al. Topiramate: long-term maintenance of weight loss induced by a low-calorie diet in obese subjects. Obes Res. 2004; 12:1658–1669.

73. Bray GA, Hollander P, Klein S, Kushner R, Levy B, Fitchet M, Perry BH. A 6-month randomized, placebo-controlled, dose-ranging trial of topiramate for weight loss in obesity. Obes Res. 2003; 11:722–733.

74. Rosenstock J, Hollander P, Gadde KM, Sun X, Strauss R, Leung A. OBD-202 Study Group A randomized, double-blind, placebo-controlled, multicenter study to assess the efficacy and safety of topiramate controlled release in the treatment of obese type 2 diabetic patients. Diabetes Care. 2007; 30:1480–1486.

75. Stenlof K, Rossner S, Vercruysse F, Kumar A, Fitchet M, Sjostrom L. Topiramate in the treatment of obese subjects with drug-naive type 2 diabetes. Diabetes Obes Metab. 2007; 9:360–368.

76. Tonstad S, Tykarski A, Weissgarten J, Ivleva A, Levy B, Kumar A, Fitchet M. Efficacy and safety of topiramate in the treatment of obese subjects with essential hypertension. Am J Cardiol. 2005; 96:243–251.

77. Toplak H, Hamann A, Moore R, Masson E, Gorska M, Vercruysse F, et al. Efficacy and safety of topiramate in combination with metformin in the treatment of obese subjects with type 2 diabetes: a randomized, double-blind, placebo-controlled study. Int J Obes. 2007; 31:138–146.

78. Wilding J, Van Gaal L, Rissanen A, Vercruysse F, Fitchet M. A randomized double-blind placebo-controlled study of the long-term efficacy and safety of topiramate in the treatment of obese subjects. Int J Obes Relat Metab Disord. 2004; 28:1399–1410.

79. Danielsson BR, Lansdell K, Patmore L, Tomson T. Effects of the antiepileptic drugs lamotrigine, topiramate and gabapentin on hERG potassium currents. Epilepsy Res. 2005; 63:17–25.

80. Lathers CM, Schraeder PL. Clinical pharmacology: drugs as a benefit and/or risk in sudden unexpected death in epilepsy? J Clin Pharmacol. 2002; 42:123–136.

81. Shorvon SD. Safety of topiramate: adverse events and relationships to dosing. Epilepsia. 1996; 37:(Suppl 2):S18–S22.

82. Puscas I, Coltau M, Baican M, Domuta G, Hecht A. Vasodilatory effect of diuretics is dependent on inhibition of vascular smooth muscle carbonic anhydrase by a direct mechanism of action. Drugs Exp Clin Res. 1999; 25:271–279.

83. Puscas I, Gilau L, Coltau M, Pasca R, Domuta G, Baican M, Hecht A. Hypotensive effect of calcium channel blockers is parallel with carbonic anhydrase I inhibition. Clin Pharmacol Ther. 2000; 68:443–449.

84. Allison DB, Gadde KM, Garvey WT, Peterson C, Schwiers ML, Najarian T, et al. Controlled-release phentermine/topiramate in severely obese adults: a randomized controlled trial (EQUIP). Obesity (Silver Spring). 2012; 20:330–342.

85. Davidson MH, Tonstad S, Oparil S, Schwiers M, Day WW, Bowden CH. Changes in cardiovascular risk associated with phentermine and topiramate extended-release in participants with comorbidities and a body mass index ≥27 kg/m2. Am J Cardiol. 2013; 111:1131–1138.

86. Gadde KM, Allison DB, Ryan DH, Peterson CA, Troupin B, Schwiers ML, Day WW. Effects of low-dose, controlled-release, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet. 2011; 377:1341–1352.

87. Garvey WT, Ryan DH, Look M, Gadde KM, Allison DB, Peterson CA, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr. 2012; 95:297–308.

88. Jordan J, Troupin BT. Cardiovascular effects and weight loss in three 1-year, double-blind, placebo-controlled clinical trials with extended-release phentermine/topiramate in obese patients. Presented at the 22nd Annual Congress of the European Society of Hypertension (ESH). London, UK; April 2012.

89. Jordan J, Astrup A, Day W. Cardiovascular safety of phentermine alone and in combination with topiramate. Presented at the 19th Annual European Congress on Obesity (ECO). Lyon, France; May 2012.

90. Bays H. Phentermine, topiramate and their combination for the treatment of adiposopathy (‘sick fat’) and metabolic disease. Expert Rev Cardiovasc Ther. 2010; 8:1777–1801.

91. Dallas, TX, USA,Brownell KD. The LEARN program for weight management. 10th ed 2004; American Health Publishing Company,

92. U.S. Food and Drug Administration. Briefing Information for the February 22, 2012 Meeting of the Endocrinologic and Metabolic Drugs Advisory Committee (WWW document). ; 2012. http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm292314.htm

http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/EndocrinologicandMetabolicDrugsAdvisoryCommittee/ucm292314.htm


93. Davidson M, Bowden CH, Day WW. Weight loss and cardiovascular risk reduction over 2 years with controlled-release phentermine-topiramate. Presented at the 60th Annual Scientific Session and Expo of the American College of Cardiology (ACC). New Orleans; April 2011.

94. White WB. Heart rate and the rate-pressure product as determinants of cardiovascular risk in patients with hypertension. Am J Hypertens. 1999; 12:(2 Pt 2):50S–55S.

95. U.S. Food and Drug Administration. FDA approves weight-management drug Qsymia [news release] (WWW document). ; July 17, 2012. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm312468.htm


96. VIVUS, Inc. VIVUS Receives Decision Regarding Qsiva Appeal [press release] (WWW document). ; February 21, 2013. http://ir.vivus.com/releasedetail.cfm

http://ir.vivus.com/releasedetail.cfm?ReleaseID = 742340.


Keywords

cardiovascular risk; obesity; phentermine; topiramate

Back to Top | Article Outline

Supplemental Digital Content

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivitives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/3.0.

© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins

Login

Search for Similar Articles
You may search for similar articles that contain these same keywords or you may modify the keyword list to augment your search.